tbuckley/cabot-search huggingface dataset:
Dysadherin awakens mechanical forces and promotes colorectal cancer progression
Authors: So-Yeon Park, Choong-Jae Lee, Jang-Hyun Choi, Jee-Heun Kim, Won-Jae Lee, Tae-Young Jang, So-El Jeon, Jae-Hyun Kim, Sang-Hee Cho, Ji-Shin Lee, Jeong-Seok Nam
Journal: Theranostics (2022)

Rationale: Dysadherin is a tumor-associated, membrane-embedded antigen found in multiple types of cancer cells, and associated with malignant behavior of cancer cells; however, the fundamental molecular mechanism by which dysadherin drives aggressive phenotypes of cancer is not yet fully determined. Methods: To get a mechanistic insight, we explored the physiological relevance of dysadherin on intestinal tumorigenesis using dysadherin knockout mice and investigated its impact on clinicopathological features in patients with advanced colorectal cancer (CRC). Next, to discover the downstream signaling pathways of dysadherin, we applied bioinformatic analysis using gene expression data of CRC patient tumors and dysadherin knockout cancer cells. Additionally, comprehensive proteomic and molecular analyses were performed to identify dysadherin-interacting proteins and their functions. Results: Dysadherin deficiency suppressed intestinal tumorigenesis in both genetic and chemical mouse models. Moreover, increased dysadherin expression in cancer cells accounted for shorter survival in CRC patients. Comprehensive bioinformatics analyses suggested that the effect of dysadherin deletion is linked to a reduction in the extracellular matrix receptor signaling pathway. Mechanistically, the extracellular domain of dysadherin bound fibronectin and enhanced cancer cell adhesion to fibronectin, facilitating the activation of integrin-mediated mechanotransduction and leading to yes-associated protein 1 activation. Dysadherin-fibronectin interaction promoted cancer cell growth, survival, migration, and invasion, effects collectively mediated the protumor activity of dysadherin. Conclusion: Our results highlight a novel function of dysadherin as a driver of mechanotransduction that stimulates CRC progression, providing a potential therapy strategy for CRC.
Selective brain entry of lipid nanoparticles in haemorrhagic stroke is linked to biphasic blood-brain barrier disruption
Authors: Zahraa S. Al-Ahmady, Ben R. Dickie, Isabelle Aldred, Dhifaf A. Jasim, Jack Barrington, Michael Haley, Eloise Lemarchand, Graham Coutts, Satinderdeep Kaur, Jessica Bates, Sarah Curran, Ruth Goddard, Megan Walker, Adrian Parry-jones, Kostas Kostarelos, Stuart M. Allan
Journal: Theranostics (2022)

Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. Methods: Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI. Results: Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (Ktrans [min-1]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. Discussion: Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules.
Single-cell profiling of microenvironment components by spatial localization in pancreatic ductal adenocarcinoma
Authors: Song Han, Dongtao Fu, Gerik W Tushoski, Lingsong Meng, Kelly M. Herremans, Andrea N. Riner, Thomas J. Geoge, Zhiguang Huo, Steven J. Hughes
Journal: Theranostics (2022)

Rationale: The biology of the pancreatic ductal adenocarcinoma (PDAC) is heterogenous, but how heterogenity of the tumor microenvironment contributes to disparate patient outcomes remains essentially unstudied. Methods: A strategy employing multiplex digital spatial profiling (mplxDSP) technology was employed to evaluate the nature and dynamics of microenvironment components including cancer associated fibroblasts (CAFs) and infiltrating immune cells at the single-cell level based upon their spatial relationship within the tumor. Results: We report that myofibroblasts directly adjacent to PDAC tumors comparatively overexpress genes (BATF3, IL12B, ITGB8, CD4 and IFNAR1), constructing pathways prone to stimulating an adaptive immune response. Markers of innate immune cells (Natural Killer cells, Dendritic Cells and macrophages) are predominant in CD45+ cells immediately adjacent to PDAC tumor, however, the checkpoint protein CTLA4 is also overwhelmingly expressed, fostering tolerance. Finaly, mRNA profiling of adjacent CAFs identified clusters of genes that correlate with survival. Conclusion: CAFs and leukocytes in close proximity to PDAC significantly differ from those remote from the tumor, providing insight into microenvironment influence on immune tolerance mediated through relative populations of leukocytes and subsets of CAFs and monocytes. mRNA expression profiling of CAFs adjacent to PDAC cells may hold promise for prognostication.
Super-stable cyanine@albumin fluorophore for enhanced NIR-II bioimaging
Authors: Lang Bai, Zhubin Hu, Tianyang Han, Yajun Wang, Jiajun Xu, Guanyu Jiang, Xin Feng, Bin Sun, Xiangping Liu, Rui Tian, Haitao Sun, Songling Zhang, Xiaoyuan Chen, Shoujun Zhu
Journal: Theranostics (2022)

Near-infrared-II (NIR-II) dyes could be encapsulated by either exogenous or endogenous albumin to form stable complexes for deep tissue bioimaging.However, we still lack a complete understanding of the interaction mechanism of the dye@albumin complex.Studying this principle is essential to guide efficient dye synthesis and develop NIR-II probes with improved brightness, photostability, etc. Methods: Here, we screen and test the optical and chemical properties of dye@albumin fluorophores, and systematically investigate the binding sites and the relationship between dye structures and binding degree.Super-stable cyanine dye@albumin fluorophores are rationally obtained, and we also evaluate their pharmacokinetics and long-lasting NIR-II imaging abilities.Results: We identify several key parameters of cyanine dyes governing the supramolecular/covalent binding to albumin, including a six-membered ring with chlorine (Cl), the small size of side groups, and relatively high hydrophobicity.The tailored fluorophore (IR-780@albumin) exhibits much-improved photostability, serving as a long-lasting imaging probe for NIR-II bioimaging. Conclusion:Our study reveals that the chloride-containing cyanine dyes with the above-screened chemical structure (e.g.IR-780) could be lodged into albumin more efficiently, producing a much more stable fluorescent probe.Our finding partly solves the photobleaching issue of clinically-available cyanine dyes, enriching the probe library for NIR-II bioimaging and imaging-guided surgery.
Sequentially targeting and intervening mutual Polo-like Kinase 1 on CAFs and tumor cells by dual targeting nano-platform for cholangiocarcinoma treatment
Authors: Yue Zhou, Lei Xu, Zhangding Wang, Hongwen Liu, Xiang Zhang, Chuanjun Shu, Meng Zhang, Ting Wang, Xinyun Xu, Xiaohong Pu, Jian He, Pin Wang, Yudong Qiu, Guifang Xu, Xiaoping Zou, Yun Zhu, Lei Wang
Journal: Theranostics (2022)

Rationale: Synergistic treatment strategies for two or more drugs have gradually developed as the main options in clinics for cholangiocarcinoma (CCA) owing to the complicated crosstalk between the tumor and stroma. However, the different synergetic mechanisms pose great challenges to the dosages and order of administration of drugs. Thus, a strategy for exploring and intervening in mutual targets derived from stromal cells and cholangiocarcinoma cells was proposed. Methods: Genes with overexpression patterns in tumors and displaying a significant association with overall survival were identified from RNA-seq data of human CCA patients and CCA mouse models. Western blotting, qRT-PCR, immunofluorescence (IF), colony formation and flow cytometry assays were conducted to determine the biological roles of the key oncogene in cholangiocarcinoma and stromal cells respectively. Additionally, a dual-targeting drug delivery system (AA-HA-ODA) for cancer-associated fibroblasts (CAFs) and tumor cells was constructed to verify the effectiveness of intervening the screened genes in vivo. Results: Polo-like kinase 1 (PLK1) was verified to play vital role in the malignant proliferation of CCA by regulating the cell cycle pathway. PLK1 also decreased stromal production by regulating the CAF phenotype. In addition, a PLK1 inhibitor (Ro3280) loaded dual-targeting drug delivery system (AA-HA-ODA) was prepared and exhibited high affinity for CAFs and cholangiocarcinoma cells. The in vivo distribution pattern and antitumor efficacy of AA-HA-ODA/Ro also verify the effectiveness of inhibiting PLK1 in CCA in vivo. Conclusion: In summary, PLK1 is a mutual target derived from tumor cells and stroma due to its crucial role in the proliferation of tumor cells and stroma regulation in CAFs, which might provide enlightenment for multitarget treatment strategies and guidance for clinical cholangiocarcinoma treatment.
Advanced nanocarrier- and microneedle-based transdermal drug delivery strategies for skin diseases treatment
Authors: Fei Qu, Rui Geng, Yijing Liu, Jintao Zhu
Journal: Theranostics (2022)

Skin diseases are the fourth leading cause of nonfatal and chronic skin diseases, acting as a global burden and affecting the world economy. Skin diseases severely impact the patients' quality of life and have influenced their physical and mental state. Treatment of these skin disorders with conventional methods shows a lack of therapeutic efficacy, long treatment duration, recurrence of the condition, and systemic side effects due to improper drug delivery. However, these pitfalls can be overcome with the applications of advanced nanocarrier- and microneedle (MN)-based transdermal drug delivery strategies that provide efficient site-specific drug delivery at the target site. These advanced transdermal drug delivery strategies can be more effective than other drug administration routes by avoiding first-pass metabolism, enhancing the drug concentration in local skin lesions, and reducing systemic toxicity. Compared with traditional transdermal delivery methods, nanocarrier- or MN-based drug delivery systems are painless, noninvasive, or minimum-invasive and require no expensive equipment. More importantly, they can introduce more advanced functions, including increased skin penetration efficiency, controlled drug release rates, enhanced targeting abilities, and theranostic functions. Here, the emergence of versatile advanced transdermal drug delivery systems for the transdermal delivery of various drugs is reviewed, focusing on the design principles, advantages, and considerations of nanocarrier- and MN-based transdermal drug delivery strategies and their applications in treating diverse skin diseases, including psoriasis, dermatitis, melanoma, and other skin diseases. Moreover, the prospects and challenges of advanced transdermal delivery strategies for treating dermatological disorders are summarized.
Wnt4 is crucial for cardiac repair by regulating mesenchymal-endothelial transition via the phospho-JNK/JNK
Authors: Wenyan Dong, Yue Zhao, Daqiang Wen, Yingjiong Lin, Chui Zeng, Jingkai Gu, Fan Liao, Ruiqi Li, Xu Zhang, Dianliang Wang, Wenqian Cai, Jinzhu Duan
Journal: Theranostics (2022)

Rational: Wnt4 plays a critical role in development and is reactivated during fibrotic injury; however, the role of Wnt4 in cardiac repair remains unclear.In this study, our aim was to clarify the pathophysiological role and mechanisms of Wnt4 following acute cardiac ischemic reperfusion injury. Methods and results:We investigated the spatio-temporal expression of Wnt4 following acute cardiac ischemic reperfusion injury and found that Wnt4 was upregulated as an early injury response gene in cardiac fibroblasts near the injury border zone and associated with mesenchymal-endothelial transition (MEndoT), a beneficial process for revascularizing the damaged myocardium in cardiac repair.Using ChIP assay and in vitro and in vivo loss-and gain-of-function, we demonstrated that Wnt4 served as a crucial downstream target gene of p53 during MEndoT.Wnt4 knockdown in cardiac fibroblasts led to decreased MEndoT and worsened cardiac function.Conversely, Wnt4 overexpression in cardiac fibroblasts induced MEndoT in these cells via the phospho-JNK/JNK signaling pathway; however, both the p53 and Wnt4 protein levels were dependent on the β-catenin signaling pathway.JNK activation plays a critical role in the induction of MEndoT and is crucial for Wnt4 regulated MEndoT.Moreover, Wnt4 overexpression specifically in cardiac fibroblasts rescued the cardiac function worsening due to genetic p53 deletion by decreasing fibrosis and increasing MEndoT and vascular density. Conclusion:Our study revealed that Wnt4 plays a pivotal role in cardiac repair with involvement of phospho-JNK mediated MEndoT and is a crucial gene for cardiac fibroblast-targeted therapy in heart disease.
FGFR blockade boosts T cell infiltration into triple-negative breast cancer by regulating cancer-associated fibroblasts
Authors: Yushen Wu, Ziying Yi, Jie Li, Yuxian Wei, Rui Feng, Jiazhou Liu, Jiefeng Huang, Yuru Chen, Xiaoyu Wang, Jiazheng Sun, Xuedong Yin, Yunhai Li, Jingyuan Wan, Li Zhang, Jing Huang, Huimin Du, Xiaoyi Wang, Qin Li, Guosheng Ren, Hongzhong Li
Journal: Theranostics (2022)

Background: Since T cell exclusion contributes to tumor immune evasion and immunotherapy resistance, how to improve T cell infiltration into solid tumors becomes an urgent challenge. Methods: We employed deep learning to profile the tumor immune microenvironment (TIME) in triple negative breast cancer (TNBC) samples from TCGA datasets and noticed that fibroblast growth factor receptor (FGFR) signaling pathways were enriched in the immune-excluded phenotype of TNBC. Erdafitinib, a selective FGFR inhibitor, was then used to investigate the effect of FGFR blockade on TIME landscape of TNBC syngeneic mouse models by flow cytometry, mass cytometry (CyTOF) and RNA sequencing. Cell Counting Kit-8 (CCK-8) assay and transwell migration assay were carried out to detect the effect of FGFR blockade on cell proliferation and migration, respectively. Cytokine array, western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) were employed to investigate the potential mechanism by which FGFR inhibition enhanced T cell infiltration. Results: Blocking FGFR pathway by Erdafitinib markedly suppressed tumor growth with increased T cell infiltration in immunocompetent mouse models of TNBC. Mechanistically, FGFR blockade inhibited cancer-associated fibroblasts (CAFs) proliferation, migration and secretion of vascular cell adhesion molecule 1 (VCAM-1) by down-regulating MAPK/ERK pathway in CAFs, thus promoting T cell infiltration by breaking physical and chemical barriers built by CAFs in TIME. Furthermore, we observed that FGFR inhibition combined with immune checkpoint blockade therapy (ICT) greatly improved the therapeutic response of TNBC tumor models. Conclusions: FGFR blockade enhanced ICT response by turning immune "cold" tumor into "hot" tumor, providing remarkable implications of FGFR inhibitors as adjuvant agents for combinatorial immunotherapy.
KDM4 inhibitor SD49-7 attenuates leukemia stem cell <i>via</i> KDM4A/MDM2/p21<sup>CIP1</sup> axis
Authors: Yinghui Li, Chaoqun Wang, Huier Gao, Jiali Gu, Yiran Zhang, Yingyi Zhang, Min Xie, Xuelian Cheng, Ming Yang, Wenshan Zhang, Yafang Li, Mei He, Hui Xu, Hexiao Zhang, Qing Ji, Tianhua Ma, Sheng Ding, Yu Zhao, Yingdai Gao
Journal: Theranostics (2022)

Rationale:Traditional treatments for leukemia fail to address stem cell drug resistance characterized by epigenetic mediators such as histone lysine-specific demethylase 4 (KDM4).The KDM4 family, which acts as epigenetic regulators inducing histone demethylation during the development and progression of leukemia, lacks specific molecular inhibitors.Methods: The KDM4 inhibitor, SD49-7, was synthesized and purified based on acyl hydrazone Schiff base.The interaction between SD49-7 and KDM4s was monitored in vitro by surface plasma resonance (SPR).In vitro and in vivo biological function experiments were performed to analyze apoptosis, colony-formation, proliferation, differentiation, and cell cycle in cell sub-lines and mice.Molecular mechanisms were demonstrated by RNA-seq, ChIP-seq, RT-qPCR and Western blotting.Results: We found significantly high KDM4A expression levels in several human leukemia subtypes.The knockdown of KDM4s inhibited leukemogenesis in the MLL-AF9 leukemia mouse model but did not affect the survival of normal human hematopoietic cells.We identified SD49-7 as a selective KDM4 inhibitor that impaired the progression of leukemia stem cells (LSCs) in vitro.SD49-7 suppressed leukemia development in the mouse model and patient-derived xenograft model of leukemia.Depletion of KDM4s activated the apoptosis signaling pathway by suppressing MDM2 expression via modulating H3K9me3 levels on the MDM2 promoter region. Conclusion:Our study demonstrates a unique KDM4 inhibitor for LSCs to overcome the resistance to traditional treatment and offers KDM4 inhibition as a promising strategy for resistant leukemia therapy.
Current update on theranostic roles of cyclophilin A in kidney diseases
Authors: Sudarat Hadpech, Visith Thongboonkerd
Journal: Theranostics (2022)

Cyclophilin A (CyPA) or peptidylprolyl isomerase A (PPIA), an immunophilin with peptidyl-prolyl cis/trans isomerase (PPIase) activity, is an abundant cellular protein widely expressed across various cell types and tissues, including the kidney. Expression of CyPA in the kidney is relatively higher in proximal tubular epithelial cells than others along the nephron. Alterations in expression and secretion of CyPA play important roles in physiological processes and pathophysiology of several diseases affecting the kidney. Herein, we provide a brief overview of CyPA structural biology and present the current update on its theranostic roles in various kidney diseases, including diabetic nephropathy, acute kidney injury, chronic kidney disease, renal fibrosis, and nephrotoxicity associated with organ transplantation. Notably, the diagnostic/prognostic role for urinary CyPA in several of these kidney diseases is promising. Finally, future perspectives on the CyPA research, especially targeting CyPA for therapeutics, are discussed. A comprehensive understanding of the theranostic roles of CyPA in kidney diseases is expected to provide novel insights into the design of new therapeutic interventions and prevention strategies.
Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling
Authors: Baoai Han, He Zhang, Ruinan Tian, Hui Liu, Zhaosong Wang, Zhiyong Wang, Jianfei Tian, Yanfen Cui, Sixin Ren, Xiaoyan Zuo, Ran Tian, Ruifang Niu, Fei Zhang
Journal: Theranostics (2022)

Rationale: Angiogenesis is a fundamental process of tumorigenesis, growth, invasion and metastatic spread.Extracellular vesicles, especially exosomes, released by primary tumors promote angiogenesis and cancer progression.However, the mechanism underlying the pro-angiogenic potency of cancer cell-derived exosomes remains poorly understood.Methods: Exosomes were isolated from breast cancer cells with high metastatic potential (HM) and low metastatic potential (LM).The pro-angiogenic effects of these exosomes were evaluated by in vitro tube formation assays, wound healing assays, rat arterial ring budding assays and in vivo Matrigel plug assays.Subsequently, RNA sequencing, shRNA-mediated gene knockdown, overexpression of different EPHA2 mutants, and small-molecule inhibitors were used to analyze the angiogenesis-promoting effect of exosomal EPHA2 and its potential downstream mechanism.Finally, xenograft tumor models were established using tumor cells expressing different levels of EPHA2 to mimic the secretion of exosomes by tumor cells in vivo, and the metastasis of cancer cells were monitored using the IVIS Spectrum imaging system and Computed Tomography.Results: Herein, we demonstrated that exosomes produced by HM breast cancer cells can promote angiogenesis and metastasis.EPHA2 was rich in HM-derived exosomes and conferred the pro-angiogenic effect.Exosomal EPHA2 can be transferred from HM breast cancer cells to endothelial cells.Moreover, it can stimulate the migration and tube-forming abilities of endothelial cells in vitro and promote angiogenesis and tumor metastasis in vivo.Mechanistically, exosomal EPHA2 activates the AMPK signaling via the ligand Ephrin A1-dependent canonical forward signaling pathway.Moreover, inhibition of the AMPK signaling impairs exosomal EPHA2-mediated pro-angiogenic effects.Conclusion: Our findings identify a novel mechanism of exosomal EPHA2-mediated intercellular communication from breast cancer cells to endothelial cells in the tumor microenvironment to provoke angiogenesis and metastasis.Targeting the exosomal EPHA2-AMPK signaling may serve as a potential strategy for breast cancer therapy.